{"doi":"10.1093/ibd/izaa161","title":"Inhibition of APE1/Ref-1 Redox Signaling Alleviates Intestinal Dysfunction and Damage to Myenteric Neurons in a Mouse Model of Spontaneous Chronic Colitis","abstract":"BACKGROUND: Inflammatory bowel disease (IBD) associates with damage to the enteric nervous system (ENS), leading to gastrointestinal (GI) dysfunction. Oxidative stress is important for the pathophysiology of inflammation-induced enteric neuropathy and GI dysfunction. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a dual functioning protein that is an essential regulator of the cellular response to oxidative stress. In this study, we aimed to determine whether an APE1/Ref-1 redox domain inhibitor, APX3330, alleviates inflammation-induced oxidative stress that leads to enteric neuropathy in the Winnie murine model of spontaneous chronic colitis. METHODS: Winnie mice received APX3330 or vehicle via intraperitoneal injections over 2 weeks and were compared with C57BL/6 controls. In vivo disease activity and GI transit were evaluated. Ex vivo experiments were performed to assess functional parameters of colonic motility, immune cell infiltration, and changes to the ENS. RESULTS: Targeting APE1/Ref-1 redox activity with APX3330 improved disease severity, reduced immune cell infiltration, restored GI function ,and provided neuroprotective effects to the enteric nervous system. Inhibition of APE1/Ref-1 redox signaling leading to reduced mitochondrial superoxide production, oxidative DNA damage, and translocation of high mobility group box 1 protein (HMGB1) was involved in neuroprotective effects of APX3330 in enteric neurons. CONCLUSIONS: This study is the first to investigate inhibition of APE1/Ref-1's redox activity via APX3330 in an animal model of chronic intestinal inflammation. Inhibition of the redox function of APE1/Ref-1 is a novel strategy that might lead to a possible application of APX3330 for the treatment of IBD.","journal":"Inflammatory Bowel Diseases","year":2020,"id":66857,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":49,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9648,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":354959,"name":"Rhiannon T. Filippone","orcid":null,"position":1,"is_corresponding":false},{"id":354028,"name":"Rhian Stavely","orcid":"0000-0002-5099-3704","position":2,"is_corresponding":false},{"id":354029,"name":"Ainsley M. Robinson","orcid":"0000-0003-3364-506X","position":3,"is_corresponding":false},{"id":354030,"name":"Xu Yan","orcid":"0000-0001-8547-4210","position":4,"is_corresponding":false},{"id":354031,"name":"Raquel Abalo","orcid":"0000-0002-6726-8795","position":5,"is_corresponding":false},{"id":354032,"name":"Rajaraman Eri","orcid":"0000-0003-1688-8043","position":6,"is_corresponding":false},{"id":333788,"name":"Joel C. Bornstein","orcid":"0000-0002-7518-7717","position":7,"is_corresponding":false},{"id":269873,"name":"Mark R. Kelley","orcid":"0000-0001-9472-1826","position":8,"is_corresponding":false},{"id":354033,"name":"Kulmira Nurgali","orcid":"0000-0002-2597-6929","position":9,"is_corresponding":false},{"id":354958,"name":"Lauren Sahakian","orcid":null,"position":0,"is_corresponding":true}],"reference_count":101,"raw_metadata":null,"created_at":"2026-07-18T21:14:50.590588Z","pmid":"32618996","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}